A considerable number of chemotherapeutic agents are known. Some are administered in order to selectively destroy the neoplastic cells wherever they may be and thereby cure the cancer. It is difficult to create a highly selective cytotoxic agent, as neoplastic cells often differ only slightly from normal body cells. One difference is that cancer cells exhibit uncontrolled growth and hence divide repeatedly. However treatments intended to attack dividing cells also affect tissues in which continual cell division occurs--such as the skin and hair, blood-forming tissues, and the epithelium of the gut--even though protocols which minimise these side-effects are used. Occasionally a tumour may exhibit peculiar biochemical properties (such as Sertoli cell tumours) and a specific chemotherapeutic agent can be devised to affect such cells. There is relatively little that can be done for the general class of solid tumours in which cell division is sparse or absent within the central regions of such tumours, because of an imperfect blood supply. While capillaries will tend to proliferate into hypoxic regions, adjacent uncontrolled growth may tend to cut off the supply to a newly set up circulation bed.
Cell populations which exist at low oxygen concentrations (i.e. hypoxic cells) in solid tumors appear to limit the effectiveness of both radiotherapy and conventional chemotherapy. However the existence of such hypoxic cells also offers a possible therapeutic opportunity, since such hypoxia is generally limited to solid tumour tissue. Drugs which could target hypoxic cells (the hypoxia-activated cytotoxins) would therefore be tumour-specific. Because the regions of severe hypoxia (&lt;0.01% O.sub.2) typically required for activation of bioreductive drugs constitute only a small proportion of most solid tumors, the activated cytotoxin should preferably be capable of diff-using for a limited distance. Hypoxia-selective cytotoxins (HSC's) have the potential to turn the hypoxic microenvironment of solid tumors to chemotherapeutic advantage.
A paper published in 1968--Papanastassiou, Z. B.; Bruni, R. J.; White, E. V. entitled Potential carcinolytic agents. VI. New deactivated biological alkylating agents. Experientia, 1968, 24, 325. discusses the use of certain quaternary nitrogen mustards, as deactivated biological alkylating agents. Preliminary screening against Dunning leukaemia and Walker carcinosarcoma showed some cytotoxic activity. The paper proposed activation of the compounds by thiols, with reference to diffuse tumours such as leukaemias. The paper does not suggest nor teach that these or similar compounds would be useful for releasing the cytotoxin, mechlorethamnine, selectively in hypoxic conditions such as occur within solid tumours. The high selectivity of the compounds of the present invention for hypoxic cells suggests that the mechanism is not activated by nucleophilic displacement by thiols, as was originally proposed. In fact, the compounds of the present invention proved surprisingly stable in the presence of thiols.